The invention relates to controlled-release oral drug delivery system comprising as active ingredient at least one xcex2-lactam antibiotic agent, particularly intended for the delivery of drugs having a specific absorption site.
The selection of the appropriate mode of drug administration is of major importance since the efficacy of the drug greatly depends thereon. The selection should be based upon the pharmacokinetic and pharmacodynamic properties of the drug. While emphasis should be given to pharmacokinetic parameters, such as absorption characteristics, protein binding and clearance, less concern is given to the pharmacodynamic profile of the drug, i.e. the concentration-effect relationship. In the case of antimicrobial agents, this relationship depends on three elements: the pathogen, the host and the specific antimicrobial agent. The impact of the host, apart from the pharmacokinetic properties, depends mainly on its immune system. The relationship between drug concentration and its inhibitory effect on microbial growth for a certain drug-pathogen combination can be determined in vitro. While in certain cases (e.g. aminoglycosides) elevation of drug concentration is associated with enhanced bacteriocidal potency, other cases (such as xcex2-lactam antibiotics and erythromycin) are not highly concentration-dependent. The post-antibiotic effect (PAE) of the drug is another pharmacodynamic parameter that has to be taken account of for the determination of an optimal dosage regime. The extrapolation of the in vitro data to an in vivo situation is less complex when the pathogen is located extracellularly, as in the case of xcex2-lactam susceptible microorganisms.
In assessing the properties of xcex2-lactam antibiotics in light of the principles outlined above, it has been concluded that an oral controlled-release preparation that would maintain low but effective concentrations for a prolonged period would be the suitable mode of administration of these medications. This conclusion is based on the following points: (1) The biological half-life of these agents is considerably short (about 1-2 hrs), which necessitates frequent administration; (2) Elevation of the drug concentration above a critical value which tends to be the minimal inhibitory concentration (MIC) is not associated with increased bacteriocidal potency; (3) There is a direct correlation between the time above MIC and o antimicrobial potency. There is no correlation between Area Under Curve (AUC) values and the drug""s efficacy; (4) It has been confirmed that continuous infusion is advantageous to periodic bolus administration of these agents; (5) For these drugs there is a minimal effective concentration before the bacteriocidal effect is noted; (6) With the single exception of penem antibiotics, all the xcex2-lactams exhibit either no PAE or a very short PAE; (7) High concentrations are associated with reduced potency; (8) The penetration of the drug into the tissues is not correlated to the serum concentration, i.e., elevation of serum drug concentrations will not contribute much in cases where the pathogen is located intracellularly; (9) Unlike aminoglycosides, the kinetics of the bacteriocidal effect are slow and require maintenance of drug effective concentration for a certain lag time to the onset of effect.
Hilton and Deasy [J. Pharm. Sci. 82(7):737-743 (1993)] described a controlled-release tablet of amoxicillin trihydrate based on the enteric polymer hydroxy-propylmethyl cellulose acetate succinate. This polymer suppressed the release of the drug in the presence of gastric pH but could enhance its release in the small intestine. Therefore, such a formulation cannot give the desired burst effect discussed below. Single dose studies with a panel of fasting subjects showed that the tablets had a relative bioavailability of only 64.4%, probably because the poorer absorption of amoxicillin from the distal jejunum and ileum than from the duodenum and proximal jejunum. Other pharmacokinetic parameters confirmed a lack of therapeutic advantage of these factors over an equivalent dose of conventional capsule.
Hilton and Deasy [Int. J. Pharm. 86(1):79-88 (1992)] also described a floating tablet of amoxicillin trihydrate. A bilayer tablet was initially formed in which the controlled-release drug layer consisted of amoxicillin and hydroxypropyl cellulose. This layer was bonded to a gas generating layer. However, when the two layers were joined together, the composite tablet failed to float and prematurely split along the joining of the two layers. Consequently, it was decided to abandon this approach in favor of a single-layer floating tablet. This tablet remained buoyant for 6 hours and had satisfactory in vitro sustained release. However, compared with conventional capsules in fasting humans at 500 mg equivalent dose of amoxicillin, the relative bioavailability of the tablets was 80.5% and other pharmacokinetic parameters T(0.1 xcexcg/ml) and T(0.5xcexcg/ml) corresponding to the length of time for which the serum levels remained greater than or equal to 0.1 xcexcg/ml and 0.5 xcexcg/ml, respectively, indicated lack of improved efficacy.
Uchida et al. [Chem. Pharm. Bull. 37(12):3416-3419 (1989)] described a preparation of amoxicillin microencapsulated in ethyl cellulose. These micro-capsules exhibited a sustained-release effect when administered to dogs. However, such effect could be foreseen, since the gastric pH of the dogs which were tested is considerably higher than human gastric pH (pH of about 6 in beagle dogs, compared to pH of about 2 in humans).
The amoxicillin is much less soluble at pH=6 than at pH=2. One would expect to obtain a very quick release of the drug from the same microcapsules if administered to humans. Such fast release would be identical to release from the pure drug, and not controlled.
Arancibia et al. [Int. J. Clin. Pharmacol. Ther. Toxicol. 25(2):97-100 (1987)] investigated the pharmacokinetics and bioavailability of amoxicillin trihydrate. They refer to controlled-release tablets, the composition of which is not described. In any case, no drug was detectable after 8 hours from oral administration and therefore this formulation had no advantage over conventional formulations.
The aim of this invention is therefore to provide oral controlled-release preparations of various drugs, preferably of xcex2-lactam antibiotics, and particularly the widely used amoxicillin, in order to optimize pharmacotherapy with these drugs. An important approach for such optimization is to improve patient compliance by minimizing the frequency of drug administration to once or twice a day.
The invention relates to a pharmaceutical controlled-release oral drug delivery system comprising as active ingredient at least one xcex2-lactam antibiotic agent having a specific absorption site in the small intestine in combination with a polymeric matrix, optionally further comprising additional pharmaceutically acceptable constituents, wherein at least 50% of said xcex2-lactam antibiotic agent are released from said matrix within from about 3 to about 4 hours from oral administration and the remainder of said pharmaceutical agent is released at a controlled rate.
The drug delivery system of the invention may further comprise a xcex2-lactamase inhibitor.
The polymeric matrix may comprise a hydrophilic polymer, a hydrophobic polymer or mixtures thereof.
The drug delivery system of the invention may be in any suitable dosage unit form.